Discovery of novel RORγ antagonists

Hirata Kazuyuki, Kotoku Masayuki, Hirashima Shintaro, Noguchi Masato, Shiozaki Makoto

doi:10.14894/medchem.27.3_160

<p>Th 17 cells were identified as a third subset of T helper cells and suggested to play a central role in the various autoimmune diseases such as psoriasis and rheumatoid arthritis. The RAR-related orphan receptor gamma（RORγ）is an orphan nuclear receptor expressed in Th 17 cells. Because of its essential role in controlling differentiation and function of Th 17 cells, RORγ represents a potential therapeutic target for autoimmune diseases. To discover novel RORγ antagonists, we started the structure-activity relationships （SAR）studies of compound 1, obtained from a high-throughput screening campaign. Compound 1 had moderate potency against RORγ, however, this compound had structural alerts and several drawbacks, such as poor microsomal stability in liver S 9 and CYP inhibition. To solve these challenges, we decided to optimize compound 1 by improving two drug-likeness metrics, ligand eﬃciency（LE）and fraction of sp³ carbon atoms（Fsp³）. The X-ray co-crystal structure, utilized for our structure optimization, showed a unique U-shaped bioactive conformation. The efforts to stabilize the unique conformation through conformational constraint led to the identiﬁcation of a novel RORγ antagonist 41 which had high potency against RORγ and signiﬁcantly improved metabolic stability as well as reduced CYP inhibition. The HCl salt of compound 41 was orally effective in mice.</p>

Discovery of novel RORγ antagonists

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